Process for the production of 8 α, 12-oxido-13,14,15,16-tetranorlabdane

ABSTRACT

In a process for the production of 8α,12-oxido-13,14,15,16-tetranorlabdane by dehydration of 8α,12-dihydroxy-13,14,15,16-tetranorlabdane (diol), wherein the diol is subjected to cyclizing dehydration in the presence of 5 to 80% by weight, based on the diol, of at least one alumino layer silicate selected from K catalysts which have an acid charge of less than 100 mval/100 g.

This application is a 371 of PCT/EP94/03889 filed Nov. 24, 1994,published as WO95/15320 Jun. 8, 1995.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a process for the production of8α,12-oxido-13,14,15,16-tetranorlabdane and to the use of specialalumino layer silicates for the production of8α,12-oxido-13,14,15,16-tetranorlabdane.

2. Statement of Related Art

8α,12-oxido-13,14,15,16-tetranorlabdane, hereinafter referred to asAMBROXAN®, is a valuable ambergris fragrance which is present inambergris, a metabolic secretion of the sperm whale (UllmannsEncyklopadie der technischen Chemie, Vol. 20, page 283, Verlag ChemieWeinheim 1981). AMBROXAN® can be synthesized from sclareol by oxidativeside-chain degradation and subsequent reduction of the lactone formed(sclareolide) in accordance with U.S. Pat. No. 3,050,532. The conversionof sclareolide into the odorless8α,12-dihydroxy-13,14,15,16-tetranorlabdane, hereinafter referred to inshort as diol, is carried out by methods known per se, for example byreduction with lithium aluminium hydride (Helv, Chim. Acta. 1950, 33,1310), with sodium borohydride (Chem. Abstr. 57, 7316a) or withpotassium borohydride/lithium chloride mixtures (Chem. Abstr. 94,15913q).

The cyclizing dehydration of the diol to form AMBROXAN® can be carriedout with acidic catalysts, for example p-toluene sulfonic acid,p-toluene sulfonic acid chloride, catalytic quantities of sulfuric acidand acidic ion exchangers in various solvents, for example toluene,hexane, pyridine, tetrahydrofuran or methanol, preferably at boilingtemperature.

U.S. Pat. No. 3,029,255 describes the use of β-naphthalene sulfonic acidor alumina as dehydration catalysts in the production of AMBROXAN®.Besides products and olefins, other secondary products are obtained inthis process so that the yield of AMBROXAN® is less than 77%.

JP-A-86/33184 (Takasago) describes a process for the production ofAMBROXAN® in which cyclization of the diol precursor is induced byspecial catalysts. The catalysts in question are acid-charged activebleaching earth, alumina or silica. The acids mentioned include, inparticular, sulfuric acid, phosphoric acid and polyphosphoric acid.However, the Takasago process has disadvantages in regard to

a) the conversion of educt, i.e. diol used, and/or

b) the formation of dehydration products (secondary products) and/or

c) the stereoselectivity of the ring closing reaction (extent of theformation of iso isomers of AMBROXAN®.

The above-mentioned disadvantages of the Takasago process are obviatedby the process described by applicants in earlier application WO90/12793. However, the process according to WO 90/12793 requiresrelatively high reaction temperatures and relatively large quantities ofcatalyst. In addition, the special HCl-charged catalyst cannot readilybe reused.

DESCRIPTION OF THE INVENTION

The problem addressed by the present invention was to develop a processfor the production of AMBROXAN® by cyclizing dehydration of the diolprecursor which would avoid the disadvantages of the processes knownfrom the prior art.

It has surprisingly been found that AMBROXAN® can be produced in highyields and purity if the diol precursor is subjected to cyclizingdehydration in a solvent and in the presence of 5 to 80% by weight,based on the diol, of alumino layer silicates which are selected fromthe group of K catalysts and which have an acid charge of less than 100mval/100 g.

The expression "acid charge" in the context of the present inventionapplies to that part of the total acid content of the alumino layersilicates which is only loosely bound to the solid and which can beanalytically determined by titration after elution with water. It ispointed out in this connection that the K catalysts have an additionalacid content which is ionically bound to the skeleton of the catalystand which does not dissociate off in aqueous dispersion.

The present invention relates to a process for the production of80α,12-oxido-13,14,15,16-tetranorlabdane by dehydration of8α,12-dihydroxy-13,14,15,16-tetranorlabdane (diol), in which80α,12-dihydroxy-13,14,15,16-tetranorlabdane is subjected to cyclizingdehydration in the presence of 5 to 80% by weight, based on the diol, ofalumino layer silicates which are selected from the group of K catalystsand which have an acid charge of less than 100 mval/100 g.

The process according to the invention has the advantage that thecatalyst is only used in relatively small quantities and that most ofthe catalyst can be reused. In addition, only very moderate temperaturesare required for carrying out the process according to the invention, sothat the danger of olfactorily undesirable secondary products beingformed is reduced by this particularly gentle method of production. Theabove-mentioned advantages of the process according to the invention arenot acquired at the expense of the high stereoselectivity of the ringclosing reaction known from WO 90/12793. In other words, the percentagecontent of the AMBROXAN® isomers 8-epi- and 9-epi-AMBROXAN® in theproduct is of the same order as in the process according to WO 90/12793.

Alumino layer silicates are minerals with a basic silicate structure inwhich silicate layers with partly incorporated aluminium³⁺ ions attachedto one another by dipol/dipol interactions and hydrogen bridge bonds arepresent, these two dimensionally infinite anionic layer silicates beingelectrostatically crosslinked by cations of an interlayer. The structureand composition of such layer silicates are known from the prior art andare described in the relevant literature. Examples of alumino layersilicates are talcum and clays of laminar structure, such as kaolinite,montmorillonite, bentonites and hectorites.

In the process according to the invention, the dehydration catalyst,i.e. the alumino layer silicates are used in a quantity of 5 to 80% byweight, based on the diol. In a preferred embodiment, they are used in aquantity of 15 to 35% by weight.

The ring closing reaction is carried out at temperatures in the rangefrom 20° to 130° C. and preferably at temperatures in the range from 50°to 110° C.,.

So-called K catalysts are used as dehydration catalysts in the processaccording to the invention. These catalysts are known to the expert, forexample from Nachr. Chem. Tech. Lab. 1985 (33) No. 3, page 202.Structurally, K catalysts are selected activated montmorillonitecatalysts which are produced by a special acid treatment. The Kcatalysts in question are, in particular, the types KP10, K10, KO, KS,K306, KA0, KA1, KA2 and KA3. K catalysts which per se have a higher acidcharge than 100 mval/100 g, for example KSF or KSF/0, and K catalystswhich have a low acid charge from their production, but which aresubsequently charged with such a quantity of acid that their acid chargeis above 100 mval/100 g, do not fall within the scope of the claims ofthe present invention.

The microstructure of the K catalysts is not explicitly described in theliterature. According to information from the manufacturer, however, itcan be assumed that, depending on the production parameters selected(acid concentration, temperature, pressure, reaction time), the acidicactivation of bentonite is accompanied by a dissolving process in whichthe crystal structure of the montmorillonite is specifically modified bythe dissolving out of aluminium, iron and magnesium ions (cf. ProductInformation Pamphlet "Was ist Bentonit? ( What is Bentonite?)" ofSudchemie).

If desired, the K catalysts to be used in accordance with the inventionmay be additionally charged with acid. Basically, there are noparticular limits to the type of acid used. However, hydrohalic acids,especially HCI, and also sulfuric acid and phosphoric acid areparticularly preferred. It is important to bear in mind, however, thatthe acid charge of the K catalysts used must be below 100 mval./100 gand preferably below 80 mval/100 g.

The diol is typically used in water-free form. However, a diol oftechnical quality with a water content of up to about 2% by weight mayalso be used.

The present invention also relates to the use of alumino layer silicateswhich are selected from the group of K catalysts and of which the acidcharge is less than 100 mval/100 g for the production of8α,12-oxido-13,14,15,16-tetranorlabdane by cyclizing dehydration of8α,12-dihydroxy-13,14,15,16-tetranorlabdane.

Suitable solvents for the cyclizing dehydration of the diol are, forexample, toluene and/or xylene.

The water formed during the dehydration reaction may be removed from thereaction mixture, for example by azeotropic distillation. On completionof the dehydration reaction, the reaction mixture is worked up in knownmanner.

The process according to the invention may be carried out in batches orcontinuously. The continuous version, carried out for example in afixed-bed reactor, affords the additional advantage that it does notrequire any special removal of the particulate catalyst.

The following Examples are intended to illustrate the invention withoutlimiting it in any way.

EXAMPLES

1. General

1.1. Substances used

Diol: 8α,12-dihydroxy-13,14,15,16-tetranorlabdane

Cat-1: Active bentonite, type B (a product of Erbsloh) acid content: 80mval H₂ SO₄ /100 g

Cat-2: Silicon dioxide ("Kieselgel 60", particle size <0.063 mm; aproduct of Merck) charged with sulfuric acid; acid content: 200 mval H₂SO₄ /100 g

Cat-3: Neutral aluminium oxide (a product of Riedel de Haen) chargedwith sulfuric acid; acid content: 200 mval H₂ SO₄ /100 g

Cat-4: Neutral aluminium oxide (a product of ICN) charged withhydrochloric acid; acid content: 14 mval HCI./100 g

Cat-5: Katalysator KP10 "Catalyst KP10"! (a product of Sud-Chemie AG);acid content: around 70 mval H₃ PO₄ /100 g

Cat-6: Katalysator K10 "Catalyst K10"! (a product of Sud-Chemie AG);acid content: around 0 mval H₂ SO₄ /100 g

1.2 Analysis

The products were quantified by gas chromatographic analysis (50 m WG11quartz capillary; injector temperature: 220° C.; detector temperature:250° C.; oven temperature: 80°→220° C. for a heating rate of 8°C./minute; carrier gas: nitrogen; pressure: 20 psi).

2. Description of tests

2.1. Preparation of AMBROXAN® by the process according to JP-A-86/33184

a) Comparison Example C1

51 g of n-heptanol and 2.54 g of diol were introduced into a 200 mlflask, the diol being dissolved by stirring. After the addition of 0.13g of catalyst cat-1, the flask was evacuated to a pressure of 10 mmHgand the system was slowly heated to 40° C. under that pressure. Thereaction mixture was then stirred for 3 hours at that temperature. Thecatalyst was filtered off, the filtrate was washed with aqueous sodiumcarbonate solution and the n-heptanol was subsequently distilled off invacuo.

The AMBROXAN® yield of 7.7%, based on diol used, was very small. Thecontent of dehydration products was found to be 2.5%, based on AMBROXAN®(cf. Table 1).

b) Comparison Example C2

In a two liter flask, a solution of 25.4 g of diol in 500 g of xylenewas added to a suspension of 5 g of catalyst cat-1 in 200 ml of xylene.The flask was evacuated to a pressure of 50 mmHg and the system wasslowly heated under that pressure. The reaction mixture was thenrefluxed for 4 hours, after which the catalyst was filtered off, thefiltrate was washed with aqueous sodium carbonate solution and, finally,the xylene was distilled off.

The yield of AMBROXAN® amounted to 32.2%, based on diol used. Theproduct contained 6.0%, based on AMBROXAN®, of dehydration products. Thecontent of iso isomers of AMBROXAN® was 1.0%, based on diol used (cf.Table 1).

Comparison Examples C3 to C5

The operations described for Comparison Example C2 were repeated, thereaction temperature and also the type and quantity of catalyst beingvaried. Particulars can be found in Table 2.

The data determined in Examples C3 to C5 are set out in Table 1.

2.2. Preparation of AMBROXAN® in accordance with the invention

a) Example E1

25 g of technical diol (pure diol content: 90%) were dissolved in 25 mlof toluene and 8 g of the catalyst KP10 were added to the resultingsolution which was then heated for 4 hours with stirring to 70° C. Thereaction solution was then filtered off and the catalyst was extractedunder reflux with 300 ml of toluene. The combined organic phases werethen washed with 1% nitric acid, 1% sodium hydroxide and finally with10% sodium sulfate solution. They were then concentrated in vacuo todryness.

The crude product was analyzed by gas chromatography. The datadetermined are set out in Table 1.

The catalyst recovered was reused for the cyclization of diol. Nodisadvantages were observed in regard to yield or the formation ofsecondary products.

b) Example E2

Example E1 was repeated using K10 instead of KP10 as catalyst. TheAMBROXAN® yield came to 97.7% (based on diol used). Other data can befound in Table 1.

3. Discussion

Comparison of Examples E1 and E2 according to the invention withComparison Examples C1 to C5 shows that there are distinct differencesin regard to yield and stereoselectivity. In the interests of clarity,the above-mentioned data are set out once again in Table 1. Importanttest parameters of Examples C1 to C5 and E1 and E2 are set out in Table2.

                  TABLE 1                                                         ______________________________________                                                     the iso isomer of                                                             AMBROXAN ®                                                   Example                                                                              AMBROXAN ®                                                                            8-epi   9-epi Dehydration product.sup.b)                   ______________________________________                                        C1      7.7%       N.d..sup.c)                                                                           N.d.   2.5%                                        C2     32.2%       0.9%    0.1%   6.0%                                        C3     68.1%       3.0%    0.1%  17.3%                                        C4     66.3%       0.8%    0.05% 16.1%                                        C5     N.r..sup.d) N.d.    N.d.  N.d.                                         E1     95.6%       0.14    0.22   3.0%                                        E2     97.7%       0.15    0.26   3.0%                                        ______________________________________                                         .sup.a) % by weight, based on diol used                                       .sup.b) % by weight, based on Ambroxan                                        .sup.c) N.d. = not determined                                                 .sup.d) N.r. = no reaction                                               

                  TABLE 2                                                         ______________________________________                                                          Catalyst                                                    Example  Temperature    Type   Quantity.sup.d)                                ______________________________________                                        C1        40° C. Cat-1  5%                                             C2       130° C. Cat-1  20%                                            C3       130° C. Cat-2  5%                                             C4       130° C. Cat-3  5%                                             C5        50° C. Cat-4  60%                                            E1        70° C. Cat-5  32%                                            E2        70° C. Cat-6  32%                                            ______________________________________                                         .sup.d) % by weight, based on diol used                                  

We claim:
 1. In a process for the production of8α,12-oxido-13,14,15,16-tetranorlabdane by dehydration of8α,12-dihydroxy-13,14,15,16-tetranorlabdane (diol), the improvementwherein said diol is subjected to cyclizing dehydration in the ofpresence of from about 5 to 80% weight, based on the diol, of a catalystconsisting of at least one alumino layer silicate selected from thegroup consisting of K catalysts which have an acid charge of less than100 mval/100 g.
 2. The process of claim 1 wherein the at least onealumino layer silicate is present in from about 15 to about 35% byweight.
 3. The process of claim 1 wherein the cyclizing dehydration iscarried out at a temperature of from about 20° to about 130° C.
 4. Theprocess of claim 3 wherein said temperature is from about 50° to about110° C.
 5. The process of claim 1 wherein the cyclizing dehydration iscarried out in the presence of a solvent.
 6. The process of claim 5wherein the solvent is toluene, xylene, or a mixture thereof.
 7. Theprocess of claim 1 wherein the at least one alumino layer silicate isreused following the cyclizing dehydration reaction.
 8. The process ofclaim 1 wherein the at least one alumino layer silicate is an activatedmontmorillonite catalyst.
 9. The process of claim 1 wherein the diol iswater-free or contains up to about 2% by weight of water.
 10. Theprocess of claim 1 wherein the at least one alumino layer silicate hasan acid charge of less than 80 mval/100 g.
 11. The process of claim 1wherein water formed during the cyclizing dehydration reaction isremoved by azeotropic distillation.
 12. In a process for the productionof 8α,12-oxido-13,14,15,16-tetranorlabdane by dehydration of8α,12-dihydroxy-13,14,15,16-tetranorlabdane (diol), the improvementwherein said diol is subjected to cyclizing dehydration at a temperatureof from about 20° to about 130° C. in the presence of from about 15 toabout 35% by weight, based on the diol, of a catalyst consisting of atleast one alumino layer silicate selected from the group consisting of Kcatalysts which have an acid charge of less than 80 mval/100 g, and inthe presence of a solvent, and wherein water formed during the cyclizingdehydration reaction is removed by azeotropic distillation.
 13. Theprocess of claim 12 wherein said temperature is from about 50° to about110° C.
 14. The process of claim 12 wherein the solvent is toluene,xylene, or a mixture thereof.
 15. The process of claim 12 wherein the atleast one alumino layer silicate is reused following the cyclizingdehydration reaction.
 16. The process of claim 12 wherein the at leastone alumino layer silicate is an activated montmorillonite catalyst. 17.The process of claim 12 wherein the diol is water-free or contains up toabout 2% by weight of water.